title: The endothelin A receptor mediates fibrocyte differentiation in chronic obstructive asthma. The involvement of connective tissue growth factor.
abstract: BACKGROUND
  Fibrocytes possess increased differentiability into α-smooth muscle actin (α-SMA)(+) myofibroblasts in chronic obstructive asthma (COA) and contribute to pulmonary fibrosis. Endothelin-1 (ET-1) induces matrix-associated gene expression through the ETA receptor (ETAR) and promotes fibroblast differentiation. However, the mechanism of fibrocyte differentiation remains unclear.
  
  
  OBJECTIVE
  To define the roles of the ETAR and connective tissue growth factor (CTGF) expression in fibrocytes in the development of fibrosis in COA.
  
  
  METHODS
  Blood nonadherent non-T (NANT) cells were isolated, and fibrocytes expressing CD45, collagen I, CTGF, ETAR, or α-SMA were identified by flow cytometry.
  
  
  RESULTS
  We showed the accumulation of fibrocytes in bronchial walls and overexpression of CTGF in fibrocytes from patients with COA. After being cultured, CTGF was increased in fibrocytes from patients with COA, but not from those of normal participants or patients with asthma without obstruction. Serum levels of ET-1 and the expression of the ETAR in fibrocytes were significantly higher in patients with COA compared with normal participants and patients with asthma without obstruction. Treatment with the ETAR antagonist (BQ123), but not ETBR antagonist (BQ788), reduced the expression of CTGF and α-SMA in fibrocytes and fibrocyte differentiation in patients with COA. Furthermore, treatment with BQ123 or an anti-CTGF antibody attenuated α-SMA expression induced by ET-1 in fibrocytes from normal participants.
  
  
  CONCLUSIONS
  Our findings demonstrate for the first time that the ETAR pathway is vital for CTGF expression, which results in fibrocyte differentiation in COA, and suggests that an ETAR antagonist may be a potential antifibrotic agent in preventing the development of fibrosis in patients with COA.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Weng
authors.forename: Bing-Chang
authors.initials: BC
authors.lastname: Chen
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Wang
authors.forename: Po-Hao
authors.initials: PH
authors.lastname: Feng
authors.forename: Meng-Jung
authors.initials: MJ
authors.lastname: Lee
authors.forename: Chien-Da
authors.initials: CD
authors.lastname: Huang
authors.forename: Han-Pin
authors.initials: HP
authors.lastname: Kuo
authors.forename: Chien-Huang
authors.initials: CH
authors.lastname: Lin
mesh_terms: D001249:Asthma / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002908:Chronic Disease; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis*; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D011379:Prognosis; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D044022:Receptor, Endothelin A / Q000096:biosynthesis*
chemical_list: D044022:Receptor, Endothelin A; D055513:Connective Tissue Growth Factor